Attentional ERPs in consumers of smoked and insufflated cocaine associated with neuropsychological performance.

BACKGROUND: Cocaine consumption is associated with reduced attentional event-related potentials (ERPs), namely P3a and P3b, indicating bottom-up and top-down deficits respectively. At cognitive level, these impairments are larger for faster routes of administration (e.g., smoked cocaine [SC]) than slower routes (e.g., insufflated cocaine [IC]). Here we assess these ERPs considering the route of cocaine administration. We hypothesized that SC dependent (SCD) would exhibit reduced amplitude of the P3a, while both SCD and IC dependent (ICD) would show reduced amplitude of the P3b. METHODS: We examined 25 SCD, 22 ICD matched by poly-consumption profiles, and 25 controls matched by demographic variables. We combined EEG data from the Global-Local task with behavioral data from attentional cognitive tasks. RESULTS: At the behavioral level, SCD exhibited attentional deficits in both bottom-up and top-down processes, while ICD only showed a tendency for top-down deficits. The amplitude of P3a and P3b was lower in Users groups. We observed subtle route-based differences, with larger differences in the P3a for SCD and in the P3b for ICD. Neurophysiological and behavioral data converged, with the P3a associated to bottom-up performance and P3b to top-down. CONCLUSIONS: Different routes of administration lead to distinct attentional neurocognitive profiles. Specifically, SCD showed greater attentional impairment, mainly at bottom-up/P3a, while ICD showed a trend of top-down/P3b deficits. These findings emphasize the crucial role of considering the route of administration in both clinical and research settings and support the use of attentional ERPs as valid measures for assessing attentional deficits in substance Dependence.

Potent, selective and reversible hMAO-B inhibition by benzalphthalides: Synthesis, enzymatic and cellular evaluations and virtual docking and predictive studies.

Monoaminooxidases (MAOs) are important targets for drugs used in the treatment of neurological and psychiatric disorders and particularly on Parkinson's Disease (PD). Compounds containing a trans-stilbenoid skeleton have demonstrated good selective and reversible MAO-B inhibition. Here, twenty-two (Z)-3-benzylidenephthalides (benzalphthalides, BPHs) displaying a trans-stilbenoid skeleton have been synthesised and evaluated as inhibitors of the MAO-A and MAO-B isoforms. Some BPHs have selectively inhibited MAO-B, with IC50 values ranging from sub-nM to µM. The most potent compound with IC50 = 0.6 nM was the 3',4'-dichloro-BPH 16, which showed highly selective and reversible MAO-B inhibitory activity. Furthermore, the most selective BPHs displayed a significant protection against the apoptosis, and mitochondrial toxic effects induced by 6-hydroxydopamine (6OHDA) on SH-SY5Y cells, used as a cellular model of PD. The results of virtual binding studies on the most potent compounds docked in MAO-B and MAO-A were in agreement with the potencies and selectivity indexes found experimentally. Additionally, related to toxicity risks, drug-likeness and ADME properties, the predictions found for the most relevant BPHs in this research were within those ranges established for drug candidates.

Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model.

Down syndrome (DS) is characterized by skeletal and brain structural malformations, cognitive impairment, altered hippocampal metabolite concentration and gene expression imbalance. These alterations were usually investigated separately, and the potential rescuing effects of green tea extracts enriched in epigallocatechin-3-gallate (GTE-EGCG) provided disparate results due to different experimental conditions. We overcame these limitations by conducting the first longitudinal controlled experiment evaluating genotype and GTE-EGCG prenatal chronic treatment effects before and after treatment discontinuation. Our findings revealed that the Ts65Dn mouse model reflected the pleiotropic nature of DS, exhibiting brachycephalic skull, ventriculomegaly, neurodevelopmental delay, hyperactivity, and impaired memory robustness with altered hippocampal metabolite concentration and gene expression. GTE-EGCG treatment modulated most systems simultaneously but did not rescue DS phenotypes. On the contrary, the treatment exacerbated trisomic phenotypes including body weight, tibia microarchitecture, neurodevelopment, adult cognition, and metabolite concentration, not supporting the therapeutic use of GTE-EGCG as a prenatal chronic treatment. Our results highlight the importance of longitudinal experiments assessing the co-modulation of multiple systems throughout development when characterizing preclinical models in complex disorders and evaluating the pleiotropic effects and general safety of pharmacological treatments.

The arrow of time of brain signals in cognition: Potential intriguing role of parts of the default mode network.

A promising idea in human cognitive neuroscience is that the default mode network (DMN) is responsible for coordinating the recruitment and scheduling of networks for computing and solving task-specific cognitive problems. This is supported by evidence showing that the physical and functional distance of DMN regions is maximally removed from sensorimotor regions containing environment-driven neural activity directly linked to perception and action, which would allow the DMN to orchestrate complex cognition from the top of the hierarchy. However, discovering the functional hierarchy of brain dynamics requires finding the best way to measure interactions between brain regions. In contrast to previous methods measuring the hierarchical flow of information using, for example, transfer entropy, here we used a thermodynamics-inspired, deep learning based Temporal Evolution NETwork (TENET) framework to assess the asymmetry in the flow of events, 'arrow of time', in human brain signals. This provides an alternative way of quantifying hierarchy, given that the arrow of time measures the directionality of information flow that leads to a breaking of the balance of the underlying hierarchy. In turn, the arrow of time is a measure of nonreversibility and thus nonequilibrium in brain dynamics. When applied to large-scale Human Connectome Project (HCP) neuroimaging data from close to a thousand participants, the TENET framework suggests that the DMN plays a significant role in orchestrating the hierarchy, that is, levels of nonreversibility, which changes between the resting state and when performing seven different cognitive tasks. Furthermore, this quantification of the hierarchy of the resting state is significantly different in health compared to neuropsychiatric disorders. Overall, the present thermodynamics-based machine-learning framework provides vital new insights into the fundamental tenets of brain dynamics for orchestrating the interactions between cognition and brain in complex environments.

Biology and Ecology of Delia planipalpis (Stein) (Diptera: Anthomyiidae), an Emerging Pest of Broccoli in Mexico.

Delia planipalpis (Stein) (Diptera: Anthomyiidae) is a pest of crucifers, such as broccoli, radish, cauliflower, turnip and cabbage. It has been recently described in Mexico as a significant emerging pest of broccoli. Due the lack of knowledge of this pest, the present study aimed to determine its life cycle, female sexual maturation, copulation, oviposition behavior and adult longevity. The identity of the fly in Mexico was confirmed genetically by sequencing the cytochrome oxidase subunit 1 gene (COI). The mean development time of D. planipalpis was 32-33 days on radish at 24 °C under laboratory conditions. Females became sexually mature 1-2 days after emergence, and the highest incidence of matings was recorded on the second day (60%). Under choice conditions, D. planipalpis females preferred to oviposit on radish plants, rather than broccoli plants, possibly due to the use of radish for rearing the laboratory colony. Oviposition and the mean number of eggs laid varied among the broccoli varieties, with the highest oviposition observed on the Tlaloc variety. Repeated attempts to rear the laboratory colony on broccoli plants failed. Radish-reared insects of both sexes lived longer when individualized in the adult stage (14.5-22.5 days) than when adult flies were maintained in groups (10-11 days). This study contributes to the understanding of D. planipalpis biology and provides information that can be used to establish future control strategies against this pest.

Identifying sustainability priorities among value chain actors in artisanal common octopus fisheries.

The United Nations (UN) Decade of Ocean Science highlights a need to improve the way in which scientific results effectively inform action and policies regarding the ocean. Our research contributes to achieving this goal by identifying practical actions, barriers, stakeholder contributions and resources required to increase the sustainability of activities carried out in the context of artisanal fisheries to meet UN Sustainable Development Goals (SDG) and International Year of Artisanal Fisheries and Aquaculture (IYAFA) Global Action Plan (GAP) Pillar targets. We conducted a novel 'social value chain analysis' via a participatory workshop to elicit perspectives of value chain actors and fisheries stakeholders associated with two Spanish artisanal common octopus (Octopus vulgaris) fisheries (western Asturias-Marine Stewardship Council [MSC] certified, and Galicia-non-MSC certified) about their priorities regarding sustainable octopus production and commercialization. Our adapted Rapfish sustainability framework emphasised the importance of economic, environmental, ethical, institutional, social, and technological indicators to different actors across the value chain. We mapped participants' shared sustainability priorities (e.g. integrated fisheries management, knowledge-based management, product traceability) to six Rapfish indicators, seven IYAFA Pillars and twelve SDGs to reveal how our results can inform ocean policy and actions. This identified how certification incentives and other cooperative approaches can facilitate environmental, economic and social sustainability (e.g. value-added products, price premiums for producers, gender inclusive organisations); support IYAFA priority outcomes (raised awareness, strengthened science-policy interface, empowered stakeholders, partnerships); and help to achieve UN SDG targets (e.g. SDG 14.b, SDG 17.17). The results can inform actors, stakeholders and policymakers about how different actors contribute to efforts to achieve the SDGs and how to manage priorities for sustainable actions within artisanal fisheries and their value chains. We recommend inclusive and equitable participatory knowledge transfer and governance platforms as part of the UN Decade of Ocean Science and beyond where participants can create theories of change towards sustainability involving the development of multi-sectoral ocean policies framed at the level of the value chain and supported by appropriate governance structures. Supplementary Information: The online version contains supplementary material available at 10.1007/s11160-023-09768-5.

Presence of Spodoptera frugiperda Multiple Nucleopolyhedrovirus (SfMNPV) Occlusion Bodies in Maize Field Soils of Mesoamerica.

The occlusion bodies (OBs) of lepidopteran nucleopolyhedroviruses can persist in soil for extended periods before being transported back on to the foliage for transmission to the host insect. A sensitive insect bioassay technique was used to detect OBs of Spodoptera frugiperda multiple nucleopolyhedrovirus (SfMNPV) in 186 soil samples collected from maize fields in the southern Mexican states of Chiapas, Tabasco, Campeche, Yucatán, and Quintana Roo, as well Belize and Guatemala. Overall, 35 (18.8%) samples proved positive for SfMNPV OBs. The frequency of OB-positive samples varied significantly among Mexican states and countries (p < 0.05). Between 1.7 and 4.4% of S. frugiperda larvae that consumed OB-positive samples died from polyhedrosis disease. Restriction endonuclease analysis using PstI and HindIII confirmed that the soil-derived isolates were strains of SfMNPV and that genetic diversity was evident among the isolates. The prevalence of OB-positive soil samples did not differ with altitude or extension (area) of the maize field, but it was significantly higher in fields with the presence of living maize plants compared to those containing dead plants or crop residues (p < 0.05). Georeferenced soil samples were used to identify soil types on digitized soil maps. Lithosol and Luvisol soils had a higher than average prevalence of OB-positive samples (42−45% positive) (p = 0.006), as did Andosol, Gleysol, and Vertisol soils (33−60% OB-positive), although the sample sizes were small (<5 samples) for the latter three soils. In contrast, Cambisol soils had a lower than average prevalence of OB-positive samples (5% positive). Bioassays on Acrisol, Fluvisol, Phaeozem, and Rendzina soils resulted in intermediate levels of OB-positive samples. We conclude that certain soil types may favor OB persistence and virus-mediated biological pest control. The soil is also likely to provide a valuable source of genetic diversity for the design of virus-based insecticides against this pest.

Temporal irreversibility of neural dynamics as a signature of consciousness.

Dissipative systems evolve in the preferred temporal direction indicated by the thermodynamic arrow of time. The fundamental nature of this temporal asymmetry led us to hypothesize its presence in the neural activity evoked by conscious perception of the physical world, and thus its covariance with the level of conscious awareness. We implemented a data-driven deep learning framework to decode the temporal inversion of electrocorticography signals acquired from non-human primates. Brain activity time series recorded during conscious wakefulness could be distinguished from their inverted counterparts with high accuracy, both using frequency and phase information. However, classification accuracy was reduced for data acquired during deep sleep and under ketamine-induced anesthesia; moreover, the predictions obtained from multiple independent neural networks were less consistent for sleep and anesthesia than for conscious wakefulness. Finally, the analysis of feature importance scores highlighted transitions between slow ($\approx$20 Hz) and fast frequencies (>40 Hz) as the main contributors to the temporal asymmetry observed during conscious wakefulness. Our results show that a preferred temporal direction is manifest in the neural activity evoked by conscious mentation and in the phenomenology of the passage of time, establishing common ground to tackle the relationship between brain and subjective experience.

Rapid metabolomic screening of cancer cells via high-throughput static droplet microfluidics.

Effective isolation and in-depth analysis of Circulating Tumour Cells (CTCs) are greatly needed in diagnosis, prognosis and monitoring of the therapeutic response of cancer patients but have not been completely fulfilled by conventional approaches. The rarity of CTCs and the lack of reliable biomarkers to distinguish them from peripheral blood cells have remained outstanding challenges for their clinical implementation. Herein, we developed a high throughput Static Droplet Microfluidic (SDM) device with 38,400 chambers, capable of isolating and classifying the number of metabolically active CTCs in peripheral blood at single-cell resolution. Owing to the miniaturisation and compartmentalisation capability of our device, we first demonstrated the ability to precisely measure the lactate production of different types of cancer cells inside 125 pL droplets at single-cell resolution. Furthermore, we compared the metabolomic activity of leukocytes from healthy donors to cancer cells and showed the ability to differentiate them. To further prove the clinical relevance, we spiked cancer cell lines in human healthy blood and showed the possibility to detect the cancer cells from leukocytes. Lastly, we tested the workflow on 8 preclinical mammary mouse models including syngeneic 67NR (non-metastatic) and 4T1.2 (metastatic) models with Triple-Negative Breast Cancer (TNBC) as well as transgenic mouses (12-week-old MMTV-PyMT). The results have shown the ability to precisely distinguish metabolically active CTCs from the blood using the proposed SDM device. The workflow is simple and robust which can eliminate the need for specialised equipment and expertise required for single-cell analysis of CTCs and facilitate on-site metabolic screening of cancer cells.

Proteomics profiling identifies extracellular vesicles' cargo associated with tumour cell induced platelet aggregation.

BACKGROUND: Cancer patients have an increased risk of developing venous thromboembolism, with up to 30% dying within a month of their development. Some cancer cells are known to induce platelet aggregation, and this interaction is understood to contribute to thrombosis and haematogenous metastasis. Many researchers have reported on extracellular vesicles (EVs) released from platelets. However, less is known about how cancer cells' EVs may affect platelet function. Here EVs released by triple-negative breast cancer (TNBC) cell line variants were extensively investigated in this regard. METHODS: EVs were separated from conditioned media of TNBC Hs578T and Hs578Ts(i)8 cells using filtration and ultracentrifugation and were characterised by nanoparticle tracking analysis, immunoblots, and transmission electron microscopy. Blood samples from consenting donors were procured, and their platelets collected by differential centrifugation. Light transmission aggregometry and optical microscopy evaluated the potential interaction of TNBC cells and their EVs with platelets. Global proteomic analysis was performed on the EVs, by in-solution digestion and mass spectrometry. Data analysis included the use of Perseus, FunRich, and Vesiclepedia. Immunoblotting was used as a secondary method to investigate some key EV cargo proteins identified by the global proteomics approach. RESULTS: Both TNBC cell variants induced platelet aggregation. Increasing cell numbers significantly reduced the time taken for platelet aggregation to occur. EVs released by the cells also resulted in platelet aggregation. The time to induce platelet aggregation was EV dose-dependent. Proteomics profiling and immunoblotting of the EVs' cargo identified candidate proteins (including uPAR and PDGFRß) that may be involved during this process. CONCLUSIONS: TNBC cells induce platelet aggregation. Furthermore, the cell-free EVs induced this undesirable effect. A number of EV cargo proteins were identified that may be relevant as therapeutic targets.

Development of a biosensor based on a new marine luciferase fused to an affibody to assess Her2 expression in living cells.

The development of new diagnostic tools in tumor pathology allows the optimization of individualized therapies in cancer patients. The functional optical image provides a unique opportunity to identify the pathophysiological characteristics of each tumor in a non-invasive way. Although fluorescent recombinant affibodies and nanobodies, capable of detecting certain membrane proteins present in tumor cells, has been described, the use of bioluminescent molecules is gaining a great impact in this field due to its high sensitivity. In this work, we characterize a new luciferase from the Metridia lucens copepod (MlLuc) and develop a novel bioluminescent recombinant affibody (MlLuc-aff) capable of recognizing the HER2 receptors that are overexpressed in breast cancer tumors. For this purpose, the thermostability and pH sensitivity of MlLuc1.1 were determined, showing no significant changes in the activity among temperatures between 4 and 70 °C, and with a maximum of brightness at pH 8.0. Furthermore, MlLuc-aff was able to accurately detect HER2 receptors expressed in the SK-BR-3 cells. Future applications of this new tracer can contribute to the early diagnosis of breast cancer patients and the assessment of the efficacy of the treatment.

Monkeypox outbreak in Spain: clinical and epidemiological findings in a prospective cross-sectional study of 185 cases.

BACKGROUND: Since May 2022, a new outbreak of monkeypox has been reported in several countries, including Spain. The clinical and epidemiological characteristics of the cases in this outbreak may differ from those in earlier reports. OBJECTIVES: To document the clinical and epidemiological characteristics of cases of monkeypox in the current outbreak. METHODS: We conducted a prospective cross-sectional study in multiple medical facilities in Spain to describe the cases of monkeypox in the 2022 outbreak. RESULTS: In total, 185 patients were included. Most cases started with primarily localized homogeneous papules, not pustules, in the probable area of inoculation, which could be cutaneous or mucous, including single lesions. Generalized small pustules appeared later in some of them. Heterogeneous lesions occurred during this generalized phase. All patients had systemic symptoms. Less common lesions included mucosal ulcers (including pharyngeal ulcers and proctitis) and monkeypox whitlows. Four patients were hospitalized, none died. Smallpox vaccination and well-controlled HIV disease were not associated with markers of severity. Contact during sex is the most likely mechanism of transmission. In this outbreak, cases have been described in men who have sex with men and are strongly associated with high-risk sexual behaviours. Seventy-six per cent of the patients had other sexually transmitted diseases upon screening. CONCLUSIONS: The clinical findings in this outbreak differ from previous findings and highly suggest contact transmission and initiation at the entry site. The characterization of the epidemiology of this outbreak has implications for control. What is already known about this topic? Monkeypox eruption is described as consisting of pustules. The roles of HIV and previous smallpox vaccination in the prognosis are unknown. The transmission route was initially described as respiratory droplets and was later suggested to be via sexual contact. What does this study add? Initial lesions at the probable inoculation area were homogeneous and papular (pseudopustules). Generalized small pustules appeared later in some of them. Heterogeneous lesions occurred during this generalized phase. All patients had systemic symptoms. Less common signs included mucosal ulcers (including pharyngeal ulcers and proctitis) and monkeypox whitlows. Well-controlled HIV and previous smallpox vaccination were not associated with severity. No patient died. The data support the hypothesis of transmission via contact during sex. Although this might change, the outbreak is currently limited mostly to men who have sex with men, with high-risk factors for sexually transmitted diseases.

Microdosing with psilocybin mushrooms: a double-blind placebo-controlled study.

The use of low sub-perceptual doses of psychedelics ("microdosing") has gained popularity in recent years. Although anecdotal reports claim multiple benefits associated with this practice, the lack of placebo-controlled studies severely limits our knowledge of microdosing and its effects. Moreover, research conducted in standard laboratory settings could fail to capture the motivation of individuals engaged or planning to engage in microdosing protocols, thus underestimating the likelihood of positive effects on creativity and cognitive function. We recruited 34 individuals starting to microdose with psilocybin mushrooms (Psilocybe cubensis), one of the materials most frequently used for this purpose. Following a double-blind placebo-controlled experimental design, we investigated the acute and short-term effects of 0.5 g of dried mushrooms on subjective experience, behavior, creativity (divergent and convergent thinking), perception, cognition, and brain activity. The reported acute effects were significantly more intense for the active dose compared to the placebo, but only for participants who correctly identified their experimental condition. These changes were accompanied by reduced EEG power in the theta band, together with preserved levels of Lempel-Ziv broadband signal complexity. For all other measurements there was no effect of microdosing except for few small changes towards cognitive impairment. According to our findings, low doses of psilocybin mushrooms can result in noticeable subjective effects and altered EEG rhythms, but without evidence to support enhanced well-being, creativity and cognitive function. We conclude that expectation underlies at least some of the anecdotal benefits attributed to microdosing with psilocybin mushrooms.

Natural language signatures of psilocybin microdosing.

RATIONALE: Serotonergic psychedelics are being studied as novel treatments for mental health disorders and as facilitators of improved well-being, mental function, and creativity. Recent studies have found mixed results concerning the effects of low doses of psychedelics ("microdosing") on these domains. However, microdosing is generally investigated using instruments designed to assess larger doses of psychedelics, which might lack sensitivity and specificity for this purpose. OBJECTIVES: Determine whether unconstrained speech contains signatures capable of identifying the acute effects of psilocybin microdoses. METHODS: Natural speech under psilocybin microdoses (0.5 g of psilocybin mushrooms) was acquired from thirty-four healthy adult volunteers (11 females: 32.09 ± 3.53 years; 23 males: 30.87 ± 4.64 years) following a double-blind and placebo-controlled experimental design with two measurement weeks per participant. On Wednesdays and Fridays of each week, participants consumed either the active dose (psilocybin) or the placebo (edible mushrooms). Features of interest were defined based on variables known to be affected by higher doses: verbosity, semantic variability, and sentiment scores. Machine learning models were used to discriminate between conditions. Classifiers were trained and tested using stratified cross-validation to compute the AUC and p-values. RESULTS: Except for semantic variability, these metrics presented significant differences between a typical active microdose and the inactive placebo condition. Machine learning classifiers were capable of distinguishing between conditions with high accuracy (AUC [Formula: see text] 0.8). CONCLUSIONS: These results constitute first evidence that low doses of serotonergic psychedelics can be identified from unconstrained natural speech, with potential for widely applicable, affordable, and ecologically valid monitoring of microdosing schedules.

Cumulative live birth rates in egg donor IVF cycles with or without endometrial scratching: Is there a residual effect in subsequent embryo transfers? Follow-up results of a RCT in clinical practice.

INTRODUCTION: Endometrial scratching (ES) is a simple technique that has been claimed to improve pregnancy rates in patients undergoing assisted reproduction techniques. Our objective was to acknowledge the effects of ES in subsequent embryo transfers by assessing the cumulative live birth rates (LBR) in patients undergoing egg-donor in vitro fertilization (IVF). MATERIAL AND METHODS: We performed a follow-up analysis of the cumulative reproductive outcomes of the 352 patients included in the Endoscratch Trial (NCT03108157) during the twelve months following the randomization date. We compared the outcomes of patients who underwent an ES for the second and/or successive embryo transfers versus those who did not have an ES performed, in order to determine a possible carry over effect that could lead to different LBR in these groups. RESULTS: Our analysis reveals that both groups (with and without ES performed before the first embryo transfer) had similar cumulative LBR (69.9% vs 65.9% in group A and B respectively, RR: 1.20, 95% confidence interval (CI): 0.92 - 1.22, p = 0.42). When we analyzed the results comparing patients who had received at least an ES before any of the embryo transfers during that period, we did not find any differences in LBR either (68.0% in patients with at least an ES and 67.8% in patients without ES, RR 1.00, 95%CI 0.87 - 1.16, p = 0.96). CONCLUSION: According to our results, we cannot state that ES has a long term effect on endometrial receptivity of egg recipients as cumulative LBR do not differ from those of patients who do not receive it.

Advancements in 3D Cell Culture Systems for Personalizing Anti-Cancer Therapies.

Over 90% of potential anti-cancer drug candidates results in translational failures in clinical trials. The main reason for this failure can be attributed to the non-accurate pre-clinical models that are being currently used for drug development and in personalised therapies. To ensure that the assessment of drug efficacy and their mechanism of action have clinical translatability, the complexity of the tumor microenvironment needs to be properly modelled. 3D culture models are emerging as a powerful research tool that recapitulates in vivo characteristics. Technological advancements in this field show promising application in improving drug discovery, pre-clinical validation, and precision medicine. In this review, we discuss the significance of the tumor microenvironment and its impact on therapy success, the current developments of 3D culture, and the opportunities that advancements that in vitro technologies can provide to improve cancer therapeutics.